Annals of Neurology

Essential tremor is a disabling and highly prevalent movement disorder. Deep brain stimulation of the ventral intermediate nucleus provides substantial symptom relief; however, many patients experience diminishing benefit over time. The underlying causes range from natural disease progression and worsening ataxia to, less commonly, habituation or tolerance. We performed a retrospective longitudinal analysis of 86 individuals with essential tremor who underwent unilateral ventral intermediate nu...

TDP-43 proteinopathy is a neuropathological hallmark of nearly all amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal dementia (FTD) cases. Nuclear loss of TDP-43 leads to widespread RNA misprocessing, such as the inclusion of cryptic exons that are no longer repressed by TDP-43. Notably, in-frame cryptic exons encode novel cryptic peptides that can be detected in biofluids, including that found in the HDGFL2 transcript. Here, we quantified HDGFL2 cryptic peptide and ne...

BackgroundBiomarkers of abnormal alpha-synuclein (asyn) that can be obtained with minimal invasiveness are needed. Promising data on dermal serine-129-phosphorylated alpha-synuclein (dermal-ps129-asyn) have emerged but accuracy for aggregated asyn in cerebrospinal fluid (CSF) has not been examined. ObjectiveDetermine sensitivity and specificity of dermal-ps129-asyn for neuronal asyn measured with cerebrospinal fluid asyn seed amplification assay (CSFasynSAA). MethodsCross-sectional observation...

BackgroundChitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases. MethodsTF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measur...

Body-first Lewy body disease (LBD) is hypothesized to begin in the peripheral autonomic nervous system, years before nigrostriatal involvement. Isolated REM sleep behaviour disorder (iRBD) is considered prodromal body-first LBD, but the duration of the prodromal phase remains unknown. We aimed to determine the progression rate of cardiac sympathetic denervation using [123I]meta-iodobenzylguanidine (MIBG) scintigraphy and employ the resulting curves to estimate the prodromal period of body-first ...

BackgroundMelanocortin 1 receptor (MC1R) is a key regulator of pigmentation. Previous studies have linked MC1R loss-of-function variants to increased risk for Parkinsons disease (PD); however, whether they are associated with PD progression remains unknown. Using data from the Parkinsons Progression Markers Initiative (PPMI) cohort, we aimed to test whether MC1R loss-of-function variants, especially those previously associated with an increased risk of PD, are associated with PD progression and ...

BackgroundMisdiagnoses of multiple system atrophy (MSA) and Parkinsons disease (PD) remain common due to overlapping clinical features. ObjectiveTo develop and assess a skin -synuclein seed amplification assay (Syn-SAA) for detecting pathological -synuclein and distinguishing MSA from PD. MethodsIn this blinded, cross-sectional study conducted across two laboratories, 308 skin biopsies from 117 participants were analyzed using a standardized Syn-SAA protocol. The cohort included 42 PD, 31 MSA,...

BackgroundAggregation of -synuclein is a central pathological feature of Parkinsons disease (PD), yet reliable and broadly applicable fluid biomarkers reflecting disease-relevant -synuclein biology remain limited. We aimed to establish acetylated -synuclein (Ac-Syn), the predominant proteoform in vivo, as a novel biomarker for PD and to evaluate its diagnostic utility based on a sensitive immunoassay. MethodsUsing a single molecule array technique capable of quantitatively detecting N-terminall...

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between...

Objective-synucleinopathies are clinically and biologically heterogeneous disorders lacking reliable biomarkers to assist with early diagnosis, disease progression, patient stratification, and therapeutic targeting. Genetic variation is known to impact biomarker levels, influencing their utility and interpretation in research and clinical settings. We aimed to identify common genetic modulators of biomarker levels implicated in -synucleinopathy pathogenesis. MethodsGenome-wide association studi...

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders, with the highest likelihood of long-term conversion to a clinical diagnosis of either Parkinsons disease (PD) or dementia with Lewy bodies (DLB). There is heterogeneity in the neuropathophysiology of iRBD that may have prognostic significance regarding the ultimate clinical features, and previous research has not focused on iRBD biologically defined as having neuronal synuclein disease (NSD) ...

IntroductionSex has emerged as a key factor shaping serum metabolomic profiles in idiopathic Parkinsons disease (PD). However, it remains unclear whether sex differences influence circulating metabolic signatures in patients with specific PD-related gene mutations compared to age-matched healthy controls (HCs). MethodsWe conducted an untargeted 1H NMR-based metabolomic analysis of serum in a clinically defined cohort of patients with genetic forms of PD (n = 119) and age- and sex-matched HCs (n...

Leucine-rich repeat kinase 2 (LRRK2) variants are the most common cause of inherited Parkinsons disease (PD), and the hyperactivity of the LRRK2 variants represent a validated drug target for PD. The penetration of common LRRK2 variants is incomplete, underscoring the need for molecular biomarkers that predict disease onset and guide therapeutics development. Here, we analyzed large datasets of cerebrospinal fluid (CSF) and urinary proteomics from the Parkinsons Progression Markers Initiative (P...

Environmental neurotoxins have been implicated in the pathogenesis of Parkinsons disease (PD), with Agent Orange (AO) recognized as a presumptive service-connected exposure among U.S. Veterans. However, prospective data examining potential clinical differences associated with AO exposure remain limited. We conducted a multicenter prospective cohort study of U.S. Veterans with PD to compare demographic and clinical characteristics between individuals with and without a history of AO exposure. Cl...

Glycoprotein nonmetastatic melanoma B (GPNMB), encoded by the target gene (GPNMB) of a Parkinsons disease (PD) risk locus, acts as a secreted factor mediating inflammatory effects in the context of immunity and cancer. In a neurodegenerative disease context, GPNMB is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein that misfolds and accumulates in PD. Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB, shed ...

Parkinsons disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are characterized by pathological aggregation of misfolded alpha-synuclein (Syn) in the central and peripheral nervous systems. Seed amplification assays (SAAs) can detect misfolded Syn in cerebrospinal fluid (CSF), allowing a more precise biological classification of these diseases. Translating biomarker-based diagnostics to blood represents a crucial milestone to democratize access to molecular testing, ...

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-20...

Parkinsons disease genetics remain under-characterized in East Asians. We recruited a Taiwanese case-control cohort (2,245 PD; 2,147 controls), genotyped on the Illumina NeuroBooster Array, and imputed 7.6 million variants using the Taiwan Biobank reference. Logistic-regression GWAS identified genome-wide significant signals at SNCA and MCCC1; we also observed suggestive associations at GCH1, PPARGC1A and GALNT13. Haplotype analyses delineated an East Asian SNCA risk haplotype and confirmed effe...

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they c...

Lewy body diseases (LBD) collectively share -synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries. To resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinsons disease (PD), dementia with Lewy bodies (DLB), and prodromal idiopathic REM sleep behaviour...